Mapping human microbiome drug metabolism by gut bacteria and their genes
Mapping human microbiome drug metabolism by gut bacteria and their genes
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DOI：
10.1038/s41586-019-1291-3
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发表时间：
2019-06-27
期刊：
影响因子：
64.8
通讯作者：
Goodman, Andrew L.
中科院分区：
文献类型：
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作者：
Zimmermann, Michael;Zimmermann-Kogadeeva, Maria;Goodman, Andrew L.
个人对药物的反应差异很大，由于治疗延误和不良反应，药物可能是危险和昂贵的。尽管越来越多的证据表明肠道微生物组与这种变异性有关，但所涉及的分子机制在很大程度上仍然未知。在这里，我们通过测量来自不同分支的76种人类肠道细菌代谢271种口服药物的能力，表明许多药物都被微生物化学修饰。我们将高通量遗传分析与质谱分析相结合，系统地鉴定代谢药物的微生物基因产物。这些微生物群编码的酶可以直接和显著地影响小鼠的肠道和全身药物代谢，并且可以根据其基因组内容解释人类肠道细菌和群落的药物代谢活动。微生物群的基因内容和代谢活动之间的这些因果关系将微生物群中的人际变异性与药物代谢中的人际差异联系起来，这对多种疾病适应症的医学治疗和药物开发具有影响。
Individuals vary widely in their responses to medicinal drugs, which can be dangerous and expensive owing to treatment delays and adverse effects. Although increasing evidence implicates the gut microbiome in this variability, the molecular mechanisms involved remain largely unknown. Here we show, by measuring the ability of 76 human gut bacteria from diverse clades to metabolize 271 orally administered drugs, that many drugs are chemically modified by microorganisms. We combined high-throughput genetic analyses with mass spectrometry to systematically identify microbial gene products that metabolize drugs. These microbiome-encoded enzymes can directly and substantially affect intestinal and systemic drug metabolism in mice, and can explain the drug-metabolizing activities of human gut bacteria and communities on the basis of their genomic contents. These causal links between the gene content and metabolic activities of the microbiota connect interpersonal variability in microbiomes to interpersonal differences in drug metabolism, which has implications for medical therapy and drug development across multiple disease indications.